Too much of a good thing

Inpatient hypercalcemia is most commonly associated with a malignancy, but it can be caused by other diseases and conditions as well.

Hypercalcemia can be a life-threatening emergency among hospitalized patients, requiring rapid diagnosis, targeted treatment, and care coordination among hospitalists and other specialists. Unlike mild forms of hypercalcemia that are more frequently diagnosed in the outpatient setting and may have few symptoms, higher elevations in calcium will be marked by several symptoms and require urgent care.

Inpatient hypercalcemia is most commonly associated with a malignancy and is usually a marker of more advanced disease, according to ACP Member Sarah Hartley, MD, a clinical instructor of hospital medicine at the University of Michigan. The most common paraneoplastic syndrome, it occurs in about 10% to 20% of patients with advanced cancer. “For these patients, the symptoms can include fatigue or weakness, dehydration that can end in renal failure, and severe cardiac complications such as shortened QTs and cardiac blocks,” she said.

Susan B LeGrand MD FACP and Rafael Espinal Bloise MD ACP Associate Member collaborate on patient care at the Cleveland Clinic Photo courtesy of Cleveland Clinic
Susan B. LeGrand, MD, FACP, and Rafael Espinal Bloise, MD, ACP Associate Member, collaborate on patient care at the Cleveland Clinic. Photo courtesy of Cleveland Clinic.

However, hypercalcemia can be caused by other diseases and conditions, including milk-alkali syndrome and granulomatous diseases. Whatever the cause, management of hypercalcemia in hospitalized patients requires recognition of the symptoms and timely, focused treatment. Decisions about treatment, particularly for patients with malignancy, should be made in consultation with other specialists, the patient and the family.

Hypercalcemia of malignancy

In cancer patients, hypercalcemia is most commonly associated with renal and breast cancers, myeloma, head/neck cancers, cancer of the ovary and bladder, lymphomas and squamous cells at any site, particularly in the lung, experts noted.

Complicating diagnosis, the same symptoms common to advanced cancer are also seen in hypercalcemia of malignancy: nausea, constipation, anorexia, malaise and fatigue. Higher levels of calcium may also lead to central nervous system effects such as lethargy, delirium and coma. The symptoms can worsen quickly in some patients, especially those with severe cases or more advanced cancer.

Diagnosis of hypercalcemia, beyond observation of the symptoms, requires calculating the patient's corrected calcium level by using the values for both calcium and albumin. For every gram of albumin above or below 4, the serum calcium should be corrected, down or up, respectively, by 0.8 mg/dL. Moderate hypercalcemia is diagnosed when the corrected calcium level is between 12 mg/dL and 14 mg/dL; however, in patients with cancer, the levels usually exceed 14 mg/dL. The parathyroid hormone should also be checked and will generally be low in patients with a malignancy.

Hydration is first-line therapy

Treatment of hypercalcemia in patients with cancer begins with acute treatment with hydration to bring down the calcium levels. The first-line therapy is “a lot of fluids pretty rapidly,” Dr. Hartley said. The rate of infusion is typically 200 cc/hour to 300 cc/hour, with a targeted urine output of 100 cc/hour to 150 cc/hour, she said.

The second step in treatment is use of a bisphosphonate, either pamidronate or zoledronate, while continuing to hydrate until normocalcemia has been achieved. Calcitonin can also be used as a short-term bridge to help bring the calcium level down before the bisphosphonate effects are achieved.

“Bisphosphonates take a little longer to play their role, but they actually give you calcium-lowering effects from days to weeks,” Dr. Hartley said. “That can help keep the numbers down while you start to think about whether anything else can be done.”

Therapy with bisphosphonates can serve a palliative purpose for patients with hypercalcemia of malignancy, providing some improvement in polyuria and polydypsia, central nervous system symptoms, constipation, nausea, vomiting, anorexia and malaise, according to an article in the November 2011 American Journal of Hospice & Palliative Medicine.

Because the hypercalcemia associated with malignancy is an indication of advanced disease, the decision of whether or not to treat can be a complicated one and should be based on the patient's disease stage, preferences, and benefit-to-risk ratio. The hospitalist's level of involvement may depend on an institution's protocols and the availability of specialists. Most likely, care will be shared with an oncologist.

Even with bisphosphonate therapy, the survival rate is poor—a median of 30 to 60 days. Response to bisphosphonate therapy lasts longer than to hydration alone, but the complete response is only about 15 days on average. And even with therapy, the hypercalcemia will recur. “Survival is poor and not affected by treatment. Discussion of goals of care is important,” said Susan B. LeGrand, MD, FACP, an oncologist and palliative medicine specialist at the Cleveland Clinic.

For some patients, that discussion leads to a decision not to treat. The patient and family may decide that the underlying disease cannot be treated any further and temporarily halting the hypercalcemia isn't what they wish to do, Dr. Hartley said. “It all hinges on the conversations you have with the patient about their goals.”

Hypercalcemia without a malignancy

Not all hospitalized patients with hypercalcemia have a malignancy. The once relatively uncommon milk-alkali syndrome, with its high calcium levels, is now sending more people to the hospital, according to Michael Whitaker, MD, chair of the division of endocrinology at the Mayo Clinic in Scottsdale, Ariz.

One of Dr. Whitaker's recent patients was admitted to the hospital with a calcium of 17 mg/dL, confusion, and an extremely low parathyroid hormone level. “The tip-off for diagnosis was that her serum bicarbonate level was high. We are seeing more patients with hypercalcemia associated with taking calcium carbonate and other supplements. Patients may come in very ill, with their confusion related to the hypercalcemia,” he said.

Granulomatous diseases, such as sarcoidosis and tuberculosis, can also lead to elevated calcium and symptoms. “It is important to understand why a patient's calcium level is elevated so that you give them the appropriate goal-directed therapy,” Dr. Hartley said. “They may come in to the hospital with new complaints related to sarcoidosis and in that setting may also have elevated calcium levels. In working up the diagnosis of sarcoidosis, it is important to recognize that the calcium levels can be a part of that picture.”

Hydration is also the first-line treatment for these non-cancer causes of hypercalcemia—which can include vitamin D and vitamin A intoxication and milk-alkali syndrome—in hospitalized patients. “Treatment is hydrate, hydrate, hydrate,” Dr. Whitaker said. “You have to get the fluids into them first, and then after that the treatment depends on the cause. Hydration is the one thing that will lower the calcium quickly and effectively.” It is also important, he said, to consider involving a specialist, such as an endocrinologist or oncologist, from the outset to help determine the best next step in treatment.

Hospitalists may also identify mild elevations of calcium in some of their patients. These elevations will not require urgent in-hospital care but rather a consultation with the primary care clinician. The hypercalcemia may be detected through an incidental finding on a routine blood test for a person hospitalized with another illness, such as pneumonia.

“If this is a mild elevation, the hospitalist should call the primary care doctor and talk to them about it. There would be no strong indication for acute treatment in that setting if the patient has no other strong symptoms, and the hypercalcemia was detected on an isolated reading,” Dr. Hartley said.

Patients who have been hospitalized for a parathyroidectomy due to primary hyperparathyroidism must also be monitored closely while in the hospital. A common postoperative complication following this surgery is development of hypocalcemia, a “hungry bones phenomenon,” Dr. Whitaker said.

“Once we remove the parathyroid tumor it is thought there may be a large influx of calcium into the bones that are ‘starved’ for calcium. Serum calcium levels may fall precipitously and may stay down for several days after surgery,” he said. The patient will need to remain in the hospital and be treated with oral and/or IV calcium supplements, and calcitriol, he added.

This complication is most common in patients who had severe primary hyperparathyroidism with large tumors removed surgically. “After hydration, calcium supplementation and calcitriol use, the condition usually settles down after two to three—or occasionally more—days,” he said. “It's important not to send them home immediately if they had severe parathyroid disease.”